Epilepsy: A Comprehensive Textbook
2nd Edition

The epilepsies are a complex group of disorders whose common feature is a tendency for hyperexcitability to develop in one or another region of the central nervous system (CNS). Epileptic syndromes and seizure types can be quite variable and may have many causes. Similarly, multiple underlying cellular and molecular mechanisms are likely to be responsible for various epileptiform phenomena. Much research has been, and continues to be, directed at unraveling the mechanisms underlying epileptic events, based on the premise that increased understanding will make it possible to devise either better treatment strategies or better methods to prevent epilepsy.

The hyperexcitable states that underlie the various forms of epilepsy represent complex functional changes in normal brain anatomy, physiology, and pharmacology. To begin to understand such changes, it is necessary to understand the normal brain substrate on which these alterations are occurring and the developmental patterns that result in the normal functioning. The next 15 chapters in this book are devoted to a systematic discussion of the physiology of normal brain function, organized according to the component parts that may be altered when epilepsy develops. Each chapter focuses on one broad area of neuronal activity, starting with an analysis of normal function at the system, cellular, and molecular levels, and then proceeding to a consideration of where this aspect of physiology might be perturbed to produce epilepsy and how naturally occurring forms of epilepsy might involve this system. Initial focus is on the excitability of individual neurons; detailed considerations of synaptic transmission, both excitatory and inhibitory, and synaptic modulation are then presented, followed by discussions of neuronal circuitry in the neocortex and limbic cortex, and the role of various subcortical structures on CNS excitability. Consideration is also given to the regulation of gene expression by both normal and pathologic activity in CNS pathways and the developmental aspects of CNS function. All this material serves as a basic scientific underpinning for the discussions of experimental seizure models and the human epilepsy syndromes, and also provides potential targets for the actions of antiepileptic drugs.

To study epileptic phenomena at a network, cellular, or molecular level, model systems are needed. The second half of this section provides detailed analyses of various experimental models used for studying seizures and epilepsy. Such models can be designed to mimic some forms of human epilepsy closely (see Chapters 36,37,38,39) but, as discussed in Chapter 41, no animal model can mimic all the features of any human epilepsy at this time. Alternatively, much simpler models can be developed that allow the isolation of specific individual epileptiform activity in ways that can be analyzed using a reductionist system. In fact, most of what is known about the cellular mechanisms of specific epileptiform events has been derived from studies of simplified systems and acutely provoked seizure activity. These studies were initially performed using in vivo animal models and, as techniques evolved for analyzing CNS tissue in vitro, they were extended to CNS models in acute slice preparations and cell culture. One of the challenges of modern epilepsy research is to extrapolate such findings to the more complex CNS of humans and the more complex problem of chronic epilepsy. The last chapter in this section discusses attempts at conducting such studies in humans, or at least in human tissue.

Most, if not all, forms of epilepsy develop over a defined time period. That is, at some point in time, the brain functions normally (and may be normal), but either after a specific developmental sequence or in response to some form of injury, a new state develops in which the neuronal circuits become hyperexcitable, leading to spontaneous recurrent seizures. This process, referred to as epileptogenesis, has been too little studied. Much less is currently understood about the process of epileptogenesis than about the phenomenology of seizures. At a clinical level, not much can yet be done to protect individuals who are known to be at high risk for the development of epilepsy, in comparison with what can be done to suppress seizures once they develop.

What can be said at present about the fundamental mechanisms of different forms of epilepsy? In partial epilepsy, it appears that areas of hyperexcitability are associated with some form of synaptic reorganization that occurs after brain injury. Some areas of brain seem much more susceptible than others, and the limbic structures in the mesial temporal lobe—notably the hippocampus, parahippocampal regions, subiculum, entorhinal cortex, and amygdala—seem particularly vulnerable. Neurons within epileptic areas in these structures undergo synchronous and paroxysmal depolarizations, and fire bursts of action potentials. These bursts are followed by periods of inhibition. Most often, such events occur singly, and relatively little perturbation of function can be detected. These represent “spikes” on the electroencephalogram (EEG). At times, such discharges do not remain confined in either anatomic space or time, and seizures result. More and more neurons are recruited into the hypersynchronous activity, both in local areas and, via synaptic pathways, distant areas subcortically and contralaterally. Why such events occur at all, and why they occur at any
specific point in time remains unknown. After all, even in the most severely affected individuals with epilepsy, seizures occur only intermittently.

It is known that seizure activity involves alterations in the fundamental excitability of neurons and in the synaptic connections between neurons. It is also known that seizures can be produced artificially by altering any of multiple cellular processes—for example, enhancing synaptic excitation or reducing synaptic inhibition. Thus, seizures develop by utilizing slight perturbations in normal cellular excitability or normal synaptic transmission and by utilizing normal anatomic pathways for both control and spread. The recognition of these principles has stimulated epilepsy researchers to lead inquiries into the physiology of normal cortical microanatomy, physiology, and pharmacology, and, most recently, molecular biology.

Primary generalized seizures present a different set of challenges to epilepsy researchers. Unlike the seizures of partial epilepsy, these events appear to start in diffuse bilateral brain areas all at once, and therefore do not provide a focal target for detailed examination by physiologists. In addition, many of the epileptic syndromes involving generalized seizures are the result of genetic alterations in CNS function, several of which are currently being unraveled. For example, studies of thalamic nuclei and thalamocortical circuits have provided dramatic new insights into the fundamental cellular mechanisms underlying some forms of primary generalized seizures. These are discussed in Chapter 31. Moreover, in both mouse and man, single gene mutations that can result in primary generalized epilepsy have been identified. As in the partial epilepsies, small perturbations in the basic cellular mechanisms of excitability and synaptic function are responsible for the underlying abnormal activity.

Most recently, studies of the fundamental mechanisms underlying epilepsy have progressed to the molecular level. Increased understanding of voltage-gated ion channels in excitable membranes, neurotransmitter receptors, neurotransmitter transport molecules, trophic substances, and other neuronal proteins has made it possible for some of the molecular changes associated with the epileptic state to be described. In addition, it is clear that the kind of excess excitability seen during epileptiform events is capable of inducing a number of specific genetic activation patterns in different circuits within the CNS. These are discussed in Chapters 21,22,23,24, 28, 31, 36, 37, and 41. Whether and how these molecular changes contribute to the stabilization of the epileptic state, or whether they are designed to counteract some of the hyperexcitability and suppress seizures remains to be determined. As new techniques in molecular neuroscience are applied to problems in epilepsy, it is likely that at least some of these questions will be answered.

Implicit in our understanding of the myriad possible perturbations of normal cellular anatomy, physiology, and pharmacology that can produce seizures in animals is the realization that genetic alterations in any of these processes may produce epilepsy. In fact, many examples of genetically determined epilepsy have been described in a variety of animal species, several of which closely mimic one or another form of epilepsy in humans. Much of this is reviewed in Chapter 37; the human genetic epilepsies are discussed in Chapter 18. Several major principles are emerging from these and other genetic studies, especially those related to the creation of transgenic animals with specific knockouts or abnormalities of single genes. It is clear that full-blown epileptic syndromes can occur in the context of single-gene mutations, but in some cases, other components of the genetic background can influence the phenotypic expression of hyperexcitability. In addition, different components of the epileptic phenotype can be specifically influenced by single genes, for example, EEG patterns. Among the more surprising recent results, however, is the realization that alterations in genes that had not been thought to be specific for brain function—such as those for enzymes in energy-producing pathways—can produce epileptic phenotypes. In fact, seizures are a common and surprising occurrence in many transgenic mice that were developed to study genes whose function was not thought to be related to neurologic diseases. These studies are likely to broaden our understanding of epileptic processes in the CNS and open the analysis of the epileptic state to new approaches, perhaps beyond the usual realm of traditional neuroscience. In turn, these new approaches may lead to new treatment strategies.

As mentioned at the beginning of this chapter, a fundamental premise for all this work is that an increased understanding of epileptic processes will result in new treatment strategies or new approaches to prevention. By contrast, until now, essentially all currently available drugs or other treatments for seizures have been discovered by accident or by general screening against seizure models. This is true despite dramatic advances in our understanding of normal brain function and the mechanisms underlying epileptic phenomena over the past 50 years. It appeared that this trend would be reversed when neuroscientists discovered the importance of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in epileptiform activity. Drugs could now be targeted for a specific mechanism. This led to the development of two drugs that were specifically designed to enhance the activity of GABA: Vigabatrin, which blocks GABA metabolism, and tiagabine, which blocks the reuptake of GABA after synaptic release. Although each has been demonstrated to be effective in both animal models of epilepsy and in patients with intractable partial seizures, neither drug has proved to be as valuable as first predicted, either because of unexpected toxicity or because of complex relations between different forms of GABA-mediated inhibition in different brain regions in different epilepsy syndromes. Other drugs targeted for the GABA system proved useful, but were then found to not act on the GABA system. Similarly, drugs developed specifically to dampen excitatory synaptic function have also been unsuccessful so far. Despite these caveats, however, most epilepsy researchers remain optimistic that, as our understanding of basic mechanisms of epilepsy and epileptogenesis increases, these findings will be directly applied to the clinical problem. Hopefully, within the next 5 to 10 years, new clinical approaches to seizure control and epilepsy prevention will be forthcoming.

Epilepsy is a complicated disorder involving disturbances of brain function at multiple levels. A variety of experimental models are currently being studied to gain an understanding of the fundamental system-level, cellular, and molecular mechanisms underlying different forms of epilepsy. In addition, human patients with epilepsy can be studied in ways that were not possible only several years ago, utilizing advanced imaging and new electrophysiological tools. Brain tissue from human patients, removed at surgery, can also be used to analyze underlying abnormalities. It is hoped that the increased understanding developed by these approaches will lead to new strategies for the treatment or prevention of epilepsy.